Abstract
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay. The level of nuclear TDP-43 is tightly regulated by these mechanisms, which control the amount of mRNA that may be translated. Based on the results of previous experiments, we developed an in silico model that mimics the intracellular dynamics of TDP-43 and examined TDP-43 metabolism under various conditions. We discovered an inherent trade-off in this mechanism between transcriptional redundancy, which maintains the robustness of TDP-43 metabolism, and vulnerability to specific interfering factors. These factors include an increased tendency of TDP-43 to aggregate, impaired nuclear-cytoplasmic TDP-43 transport, and a decreased efficiency of degrading abnormal proteins, all of which are functional abnormalities related to the gene that causes familial ALS/FTD. When these conditions continue at a certain intensity, the vulnerability of the autoregulatory machinery becomes apparent over time, and transcriptional redundancy enters a vicious cycle that ultimately results in TDP-43 pathology. The results obtained using this in silico model reveal the difference in TDP-43 metabolism between normal and disease states. Furthermore, using this model, we simulated the effect of a decrease in TDP-43 transcription and found that this decrease improved TDP-43 pathology and suppressed the abnormal propagation of TDP-43. Therefore, we propose a potential therapeutic strategy to suppress transcriptional redundancy, which is the driving force of the pathological condition caused by the specific factors described above, in patients with ALS presenting with TDP-43 pathology. An ALS animal model exhibiting TDP-43 pathology without overexpression of exogenous TDP-43 should be developed to investigate the effect of alleviating the transcriptional redundancy of TARDBP.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by the degeneration of upper and lower motor neurons
We show that robustness in the maintenance of nuclear TAR DNAbinding protein 43 (TDP-43) by autoregulation results in a decrease in nuclear TDP-43 and enhances aggregate accumulation through a pathological spiral driven by redundant transcription under several specific conditions
We propose that transcriptional redundancy, which is important for the strict regulation of TDP-43, is the driving force underlying the formation and progression of TDP43 pathology in patients with ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by the degeneration of upper and lower motor neurons. The half-life of the 43 kDa TDP-43 protein in this cultured cell line is approximately 30 h, the level of urea-soluble TDP-43 remains slightly reduced 48 h after MG132 wash out (Scotter et al, 2014) In this model, the degradation rate of aggregates was assumed to be 0.2 times the degradation rate of nuclear TDP43. We initially assessed a TARDBP heterozygous knockout model in which the transcription of TARDBP is reduced by half to determine whether our in silico model designed to investigate TDP-43 autoregulation produces results consistent with the findings from previous studies (Figure 3C). In the NAR (–) model, the level of nuclear TDP-43 decreased as its transcription level decreased, reaching approximately half of the initial value under conditions that mimic the TARDBP heterozygous knockout mouse model (Figure 5A). The NAR (+) model exhibited more fragility than the NAR (–) model when the parameters were set such that the efficiency of the degradation of fragmented proteins decreased (Figure 5E and Supplementary Figures 2B, 3B)
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